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R Hovorka

Publications and source records attributed to R Hovorka.

At least 37 records · Page 2Linked to original sources
PubMed1997

Constant infusion and bolus injection of stable-label tracer give reproducible and comparable fasting HGO.

We have investigated the reproducibility of fasting hepatic glucose output (HGO) estimates by use of isotope dilution methodology of stable-label tracers. Six normal subjects were studied on two occasions 1 wk apart. After an overnight fast, the subjects received a bolus injection of 7 mg/kg of [U-13C]glucose and, simultaneously, a primed constant infusion of 0.05 mg.kg-1.min-1 of [6,6(-2)H]glucose. The bolus injection provided one estimate of HGO (HGOBOL), and the constant infusion provided two estimates of HGO, namely, HGO at 2 h (HGOINF2) and HGO at 4 h (HGOINF4), both with the assumption of steady-state conditions. All estimates were similar in value; HGOBOL was highest, followed by HGOINF2 and HGOINF4 [2.30 +/- 0.11 (SE), 2.17 +/- 0.12, and 2.01 +/- 0.13 mg.kg-1.min-1]. The constant infusion gave highly reproducible results. In the case of HGOINF2, the within-subject coefficient of variation (CV) was only 3% compared with 5% of HGOINF4. The reproducibility of HGOBOL was comparable with the within-subject CV of 7%. We conclude that a constant infusion and a bolus injection of stable-label tracer give reproducible and comparable estimates of HGO.

Adult↗
PubMed1996

Quantitative measurement of 3-O-methyl-D-glucose by gas chromatography-mass spectrometry as a measure of glucose transport in vivo.

Existing methods of measuring glucose kinetics are subject to errors. There is considerable interest in improved methods of measuring glucose kinetics to allow the development of new regimes for the treatment of diabetes mellitus. 3-O-Methyl-D-glucose is transported but not metabolized and therefore allows independent estimation of transport parameters. We describe a method by which 3-O-methyl-D-glucose in plasma samples can be measured in protocols during which glucose flux is assessed with simultaneous use of two isotopically labeled glucoses to quantitate and validate measurements of the rate of glucose appearance and disappearance. Quantitative gas chromatographic/mass spectrometric (GC/MS) analysis of 3-O-methyl-D-glucose, D-glucose, D-[U-13C] glucose and D-[6,6-2H2] glucose in human plasma using methoxime-trimethylsilyl ether derivatives is described. Measurements of all four derivatives were performed together in a small sample volume (50 microliters) with high precision. The intra-assay (inter-assay) coefficients of variation at an isotope content of 0.25 atom% excess for D-[6,6-2H2] glucose, D-[U-13C] glucose and 3-O-methyl-D-glucose were 0.8% (1.0%), 0.5% (4.0%) and 0.1% (3.7%), respectively. This method provides the basis for quantitative estimation of parameters of glucose kinetics in man and the rates of glucose flux across the cell membrane.

3-O-Methylglucose↗
PubMed1996

A comparison of six deconvolution techniques.

We present results for the comparison of six deconvolution techniques. The methods we consider are based on Fourier transforms, system identification, constrained optimization, the use of cubic spline basis functions, maximum entropy, and a genetic algorithm. We compare the performance of these techniques by applying them to simulated noisy data, in order to extract an input function when the unit impulse response is known. The simulated data are generated by convolving the known impulse response with each of five different input functions, and then adding noise of constant coefficient of variation. Each algorithm was tested on 500 data sets, and we define error measures in order to compare the performance of the different methods.

Algorithms↗
PubMed1996

Analysing the hypoglycaemic counter-regulation: a clinically relevant phenomenon?

This paper describes an analysis of the temporal relation between episodes of low blood glucose (hypoglycaemia) and counter-regulations, i.e., episodes of elevated blood glucose (hyperglycaemia), in patients with insulin dependent diabetes. The relation was assessed by statistical methods based on a metabolic computer model of the human glucose metabolism. The study material was standard collected clinical data on meals, insulin injections, and measured blood glucose from hospitalised patients. We have found that a typical hypoglycaemic counter-regulation begins 6-8 h after the hypoglycaemia, that it lasts 16-18 h, giving a total duration of 24 h, and that it elevates the blood glucose by 4-10 mmol/l. The phenomenon was demonstrated in the data from more than half of the patients with hypoglycaemic episodes.

Blood Glucose↗
PubMed1996

Use of the DIAS model to predict unrecognised hypoglycaemia in patients with insulin-dependent diabetes.

The Diabetes Advisory System (DIAS) is a model of human glucose metabolism implemented in a causal probabilistic network. It handles data on insulin dose, carbohydrate intake and blood glucose concentration to predict hourly blood glucose concentrations and thus provide an indication of blood glucose values between home blood tests. DIAS was used to predict blood glucose profiles in eight patients with well-controlled insulin-dependent diabetes, who are at increased risk of hypoglycaemia (abnormally low blood glucose levels). DIAS predicted nocturnal hypoglycaemia in six patients and daytime hypoglycaemia in one patient. The occurrence of nocturnal hypoglycaemia was not recognised by the patient or suspected by their doctor but was subsequently confirmed by blood testing in five patients. It is known that unrecognised nocturnal hypoglycaemia is common in patients with well-controlled diabetes. The ability of DIAS to identify such periods of hypoglycaemia with reasonable accuracy illustrates how the advanced technology it employs may provide reliable decision support to clinicians.

Adolescent↗
PubMed1996

ISEC: a program to calculate insulin secretion.

ISEC (Insulin SECretion) is a computer program which calculates pre-hepatic insulin secretion from plasma C-peptide measurements. The program uses a regression (population) model to derive parameters of C-peptide kinetics from subject's gender, type (normal, obese, non-insulin dependent diabetes mellitus), age, weight, and height. Insulin secretion is calculated as a piece-wise constant (step) function with flexible step length allowing for a fine resolution of the secretion profile between measurements. A constrained regularisation method of deconvolution is employed to carry out the calculations. The calculated profile satisfies three properties: (i) it fits the measurement within the given level of the measurement error, (ii) it is non-negative, and (iii) it has a minimum value of a regularisation criterion (norm of second differences) which quantifies the degree of deviation of the secretion profile from a straight line. Both theoretical aspects and specific features related to ISEC are considered. To exemplify the use of ISEC, pre-hepatic insulin secretion is calculated during meal tolerance test, frequently sampled intravenous glucose tolerance test, hyperinsulinaemic euglycaemic glucose clamp, and basal conditions with frequent sampling.

Adult↗
PubMed1996

Acid-base chemistry of the blood--a general model.

This paper describes a general model of acid-base chemistry of the blood which can be used to simulate physiological perturbation of acid-base chemistry on addition or removal of any buffer acid or base. In particular, it is shown how this model can be used to estimate the concentrations of buffer acid or base. In particular, it is shown how this model can be used to estimate the concentrations of buffer acids and bases when blood is equilibrated to a new pCO2, when hydrogen ions H+ are added to the blood, or when two pools of blood with different concentrations of buffer acids and bases are mixed. The ability of the model to represent the addition or removal of any acid or base is a significant increase in functionality above the Siggaard-Andersen nomogram which is limited to simulating the effects of equilibrating the blood to a new pCO2. When used to represent the situation where blood is equilibrated at a new pCO2 the model enables calculation of the amount CO2 removed during equilibration, a further increase in functionality above the Siggaard-Andersen nomogram. In two experimental situations, equilibrating blood to a new pCO2 and addition of H+ ions, the model predictions are shown to be consistent with existing experimental data in the form of the Siggaard-Andersen nomogram.

Acid-Base Equilibrium↗
PubMed1996

Effects of intravenous infusion of lipid-free apo A-I in humans.

Apolipoprotein (apo) A-I is the principal protein component of the plasma high density lipoproteins (HDLs). Tissue culture studies have suggested that lipid-free apo A-I may, by recruiting phospholipids (PLs) and unesterified cholesterol from cell membranes, initiate reverse cholesterol transport and provide a nidus for the formation, via lipid-poor, pre-beta-migrating HDLs, of spheroidal alpha-migrating HDLs. Apo A-I has also been shown to inhibit hepatic lipase (HL) and lipoprotein lipase (LPL) in vitro. To further study its functions and fate in vivo, we gave lipid-free apo A-I intravenously on a total of 32 occasions to six men with low HDL cholesterol (30 to 38 mg/dL) by bolus injection (25 mg/kg) and/or by infusion over 5 hours (1.25, 2.5, 5.0, and 10.0 mg.kg-1.h-1). The procedure was well tolerated: there were no clinical, biochemical, or hematologic changes, and there was no evidence of allergic, immunologic, or acute-phase responses. The 5-hour infusions increased plasma total apo A-I concentration in a dose-related manner by 10 to 50 mg/dL after which it decreased, with a half-life of 15 to 54 hours. Coinfusion of Intralipid reduced the clearance rate. The apparent volume of distribution exceeded the known extracellular space in humans, suggesting extensive first-pass clearance by one or more organs. No apo A-I appeared in the urine. Increases in apo A-I mass were confined to the pre-beta region on crossed immunoelectrophoresis of plasma and to HDL-size particles on size exclusion chromatography. Increases were recorded in HDL PL, but not in HDL unesterified or esterified cholesterol. Increases also occurred in LDL PL and in very low density lipoprotein cholesterol, triglycerides, and PL but not in plasma total apo B concentration. These results can all be explained by combined inhibition of HL and LPL activities. Owing to the effects that this would have had on HDL metabolism, no conclusions can be drawn from these data about the role of lipid-free apo A-I in the removal of PL and cholesterol from peripheral tissues in humans. The kinetic data suggest that the fractional catabolic rate of lipid-free apo A-I exceeds that of spheroidal HDLs and is reduced in the presence of surplus PL.

Aged↗
PubMed1995

Retrospective testing of an insulin advisory system.

A retrospective analysis of the function of adaptive model based consultation system for insulin therapy was performed. The program proved good adaptation ability with improving blood glucose level prediction. In a group of 12 brittle type 1 diabetic patients individual analysis showed problems resulting from retrospective testing of dynamic systems, when treatment is determined only by the physician.

Blood Glucose↗
PubMed1994

A probabilistic approach to glucose prediction and insulin dose adjustment: description of metabolic model and pilot evaluation study.

A model of carbohydrate metabolism has been implemented as a causal probabilistic network, allowing explicit representation of the uncertainties involved in the prediction of 24-h blood glucose profiles in insulin-dependent diabetic subjects. The parameters of the model were based on experimental data from the literature describing insulin and carbohydrate absorption, renal loss of glucose, insulin-independent glucose utilisation and insulin-dependent glucose utilisation and production. The model can be adapted to the observed glucose metabolism in the individual patient and can be used to generate predicted 24-h blood glucose profiles. A penalty is assigned to each level of blood glucose, to indicate that high and low blood glucose levels are undesirable. The system can be asked to find the insulin doses that result in the most desirable 24-h blood glucose profile. In a series of 12 patients, the system predicted blood glucose with a mean error of 3.3 mmol/l. The insulin doses suggested by the system seemed reasonable and in several cases seemed more appropriate than the doses actually administered to the patients.

Absorption↗
PubMed1994

A simulation study to determine optimal insulin priming during glucose clamp studies.

Computer simulation of hyperinsulinaemic euglycaemic clamp studies (HECS) using a novel model of insulin kinetics shows that a priming dose of insulin should be in the form of a 10-min-long infusion at a rate six-fold higher than the intended insulin infusion rate in patients with non-insulin-dependent diabetes mellitus. Using this priming regimen, glucose uptake attains equilibrium within 90 min. Two alternative priming regimens: a priming bolus and a monoexponential-decay priming infusion, also result in equilibrium of glucose uptake within 90 min, but give higher transients of plasma insulin concentration. However, with no priming, or if a conventional priming regimen is used, glucose uptake at 90 min rises to only around 80% of its equilibrium value. We conclude that priming of insulin is essential to attain steady state of glucose uptake within 90 min of HECS and that conventionally used priming regimens result in an underestimation of glucose uptake.

Blood Glucose↗
PubMed1994

Risk calculation of type 2 diabetes.

The paper presents an analysis of the risk of developing Type 2 diabetes according to family history and anthropometric variables. The age of diabetes onset was analysed in 2024 diabetics. We obtained several groups according to family history. In each group taken separately, the data describing the cumulative percentage of diabetes onset was fitted by logistic curve F(x) = p1/(1 + p2*p3((x/10)-p4)). Comparing these curves we see that cumulative age-dependent risk increases from the group of randomly chosen persons through the group of first degree relatives to the children of diabetics. The highest risk of diabetes onset is determined by the curve representing the group of known diabetics. Another analysis was performed in a different group of 390 obese subjects (34 diabetics among them). Male diabetics had significantly higher body mass index (BMI) and weight than male non-diabetics. Female diabetics showed significantly higher weight, body mass index, waist to hip ratio (WHR) and age than female non-diabetics. Elimination of factors with randomization and matching showed a complicated relationship between diabetes, age and anthropometric variables. Using stepwise logistic regression we obtained the model for prediction of diabetes risk based on age, BMI, WHR: probability of diabetes = exp(u)/(1 + exp(u)), where u = -13.9 + 0.05431*age + 6.789*WHR + 0.07881*BMI for obese women, u = -11.84 + 10.01*WHR for obese men. In conclusion, genetic factors are the most important and can be exactly quantified in Type 2 diabetes. The importance of anthropometric variables for prediction of diabetes risk is also presented.

Adult↗
PubMed1993

Five-compartment model of insulin kinetics and its use to investigate action of chloroquine in NIDDM.

We have constructed a five-compartment model of insulin kinetics. The model structure was chosen to reflect insulin distribution in systemic plasma, hepatic plasma, and interstitial fluid and insulin binding to the liver and peripheral receptors, and it included receptor-mediated and non-receptor-mediated insulin degradation. Model parameters were estimated from plasma insulin concentrations measured during hyperinsulinemic euglycemic clamp studies. In the fasting condition, the model-derived mean residence time of endogenously secreted insulin was 71 min, of which 62 min were spent bound to the liver receptor, 6 min bound to the peripheral receptor, 2 min circulating in hepatic or systemic plasma, and 1 min in the interstitial fluid. More than 80% of total insulin was bound to the liver receptor, indicating that the liver is by far the largest insulin reservoir. The model was employed to assess the effect of chloroquine on insulin kinetics in patients with non-insulin-dependent diabetes mellitus (NIDDM). Chloroquine significantly altered parameter vector. However, the mean residence times of insulin in the system and in the periphery were not affected, indicating that the beneficial effect of chloroquine in patients with NIDDM under conditions of euglycemia could not be attributed to changes in insulin kinetics.

Chloroquine↗
PubMed1991

Identification of insulin receptor systems: assessing the impact of model selection and measurement error on precision of parameter estimates using Monte Carlo study.

An extensive Monte Carlo study has been carried out in order to study the effect of measurement error on the precision of parameter estimates of an insulin binding system. Hypothetical radioimmunoassay experiments were generated for insulin binding to erythrocytes. The design of experiments followed strictly the protocol of real experiments. Randomly generated error was added to the synthetic data. The standard technique, a weighted non-linear regression analysis, was employed to re-estimate parameters of a model of two receptor sites and a model of negative co-operativity. As the original parameter values were known, the differences between original and estimated values was studied for (a) measurement error in the range from 0-17%, (b) random initial estimates and (c) error-free non-specific binding. In addition, analytical estimates of parameter precision were compared with the true between-experiment variation of parameter estimates. At the measurement error of 12%, a one site model is recommended to estimate the high affinity population of the two sites model. Plausible results can be expected in 90% of experiments, the between-experiment variation being approximately 30%. The model of two receptor sites gives approximately two thirds of plausible results. The high affinity population can be estimated with the between-experiment variation of 40%, the low affinity population is virtually unidentifiable with the between-experiment variation of approximately 100% and parameter estimates biased to higher values. Only half of the results obtained from the model of negative co-operativity are plausible, the variation in parameter estimates ranges from 90-150% and estimates are biased to higher values. At the level of 12% measurement error, random initial estimates do not significantly affect the estimation process, provided initial estimates are selected from a feasible range. At the same measurement error, the error-free non-specific binding does not improve the results, indicating that the mean of six replicates may be taken as a reliable estimate of non-specific binding. The analytical estimates of the coefficient of variation systematically underestimates the true between-experiments coefficient of variation, the difference has been found to be about 50%.

Erythrocytes↗
PubMed1990

[Experience with a computer database in a cytogenetic laboratory].

The paper describes a computer system to support the data management in cytogenetics. Two major objectives are considered: the improvement of the quality and consistency of laboratory data and the support of data management in a large data set for research purposes. The entire system is divided into two logical parts. Firstly, a data collection module reads data from keyboard in an user-friendly way and checks for consistency including syntactic analysis of karyotype description. Secondly, the data are manipulated by a professional database system where three hierarchical data structures are introduced: 1. identification data, 2. investigation data and 3. karyotype description. Since 1984 we collected 1820 patients, 2800 investigations and 2760 karyotypes in the system. Currently, the system is reimplemented on IBM compatible machine using "dBase" database system in order to increase the operational speed and enhance the transportability of the system.

Chromosome Aberrations↗
PubMed1990

[A consulting system for insulin therapy in diabetes].

The authors describe a computer system which provides consultations on insulin treatment of diabetes. The intentions and aims of computer consultation and means for their implementation are described. The basic element of the system is the model of insulin pharmacodynamics. Two concepts are used to differentiate individual characteristics of the patient: the basal need and insulin sensitivity. The basal need is the amount of insulin which maintains the blood sugar level at the desired level in the course of the day, provided the subject adheres to a standard regime. The insulin sensitivity represents the sensitivity of the glucose metabolism to deviations from the basal requirement. These purely individual parameters are currently adapted by the "learning" module. The module compares the assessed and predicted blood sugar levels and corrects the parameters to achieve a minimum difference. The accuracy of approximation depends on the number of assessed blood sugar levels. The system foresees a minimum of two assessments per day. Individualized parameters are used for the prediction of the blood sugar level. The system visualizes predicted blood sugar levels for manually administered alternative insulin doses. The module of the automatic therapeutic plan is part of the module. The system recommends treatment with an "optimal" development of the predicted blood sugar level. As a criterium of the optimal profile of the blood sugar level the M-value was selected which is used for the evaluation of the daily blood sugar profile. The predictive capacity of the system was evaluated on the basis of retrospective data.(ABSTRACT TRUNCATED AT 250 WORDS)

Diabetes Mellitus↗
PubMed1990

[Analysis of dynamic changes in glycosylated blood proteins using a computer model].

UNLABELLED: The authors elaborated a computer model of albumin glycosylation based on the irreversible glycosylation reaction with first order kinetics. The dynamics of changes of glycosylated albumin in relation to the glycaemic profile was confirmed with an older model of haemoglobin glycosylation. By means of regression analysis parameters of the model in three groups of patients were calculated. CONCLUSION: 1. Stratification of the red cell pool is the reason why there is a smaller clinical difference between glycosylated protein and haemoglobin than corresponds to their half-times. 2. Glycosylated proteins are probably eliminated more rapidly than non-glycosylated ones. 3. Higher levels of glycosylated proteins sometimes do not correspond to model calculations are probably due to other factors.

Computer Simulation↗